The prevalence of neurodegenerative diseases is escalating at an alarming rate as life expectancy increases. During the next quarter century, the number of individuals suffering from neurodegenerative cognitive deficits is expected to rise at an alarming rate. One important goal for neuroscience is the elucidation of physiological mechanisms underlying or otherwise contributing to these pathologies. Considerable evidence suggests that the pancreatic hormone, insulin, is a key factor. Secreted in response to increased blood glucose, insulin's best-known systemic action is to facilitate uptake of energy by peripheral tissues. Recent research has focused on insulin's actions in the central nervous system as well. Receptors for insulin are selectively expressed in several brain areas, with high concentrations in the hippocampus, a brain area important for formation of certain memories. Importantly, disease states related to systemic insulin insensitivity, such as diabetes mellitus, are associated with cognitive deficits in humans and animals, and administration of insulin either peripherally or directly into the brain, can alleviate symptoms of these cognitive deficits in animal subjects. These and other data encourage the hypothesis that insulin plays an important role in normal neural function and that disruptions in insulin signaling may contribute to neurological pathologies. The long-term goal of our proposal is to elucidate the roles for central insulin receptors, particularly in the hippocampus, in cognitive processes. To accomplish this, we will investigate learning abilities in mice with selective genetic deletion of a critical region of the insulin receptor gene. Importantly, these deletions will be limited to the central nervous system or only to the hippocampus. Previous work has attempted to study the role of insulin using systemic manipulations, which can cause serious side effects and confounds. Utilization of this new transgene technology will help us eliminate those confounds and side effects, to more fully understand the role of insulin signaling in learning and memory. Ultimately, this line of investigation may offer novel therapeutic strategies for treating individuals with cognitive disorders such as Alzheimer' s disease.